Abstract
TO THE EDITOR: It has been reported that tumor necrosis factor-α (TNF-α) blockers may damage the cardiovascular system. 1 We report one patient with rheumatoid arthritis (RA) treated with a TNF-α blocker (infliximab) who developed accelerated left-ventricular diastolic dysfunction (LVDD) and pulmonary hypertension.
Case Report
In July 2003, a 62-year-old woman with a background of erosive, seropositive RA and hypertension received infliximab 200 mg, which was added to methotrexate due to the inefficacy of methotrexate. After the second infusion of infliximab, mild exertional dyspnea and fatigue began. After the third infusion (September 2003), her problems worsened, and infliximab was discontinued. On examination, the woman was afebrile and blood pressure was 150/100 mm Hg. She also had neck vein distension and mild edema of both legs. An echocardiogram showed a mild left-ventricular hypertrophy with normal systolic function and decreased transmitralic flow associated with delayed relaxation. Pulmonary artery pressure (PAP) and ejection fraction (EF) were 45 mm Hg and 71%, respectively. The patient was given perindopril and indapamide.
In November, the patient was admitted to the hospital as symptoms did not improve. No thrombosis was found in the lower veins of the legs on Doppler ultrasonography. A ventilation/perfusion scan showed no evidence of pulmonary emboli. An echocardiogram showed a mild left-ventricular hypertrophy with normal systolic function. PAP and EF were 60 mm Hg and 61%, respectively. The woman was discharged on diltiazem 90 mg/day and methotrexate 12.5 mg/wk. Dyspnea and palpitations resolved within 2 months, but 2 pretibial skin ulcerations developed. Antinuclear antibody was negative. Her biopsy showed pyoderma gangrenosum. An echocardiogram showed PAP 30 mm Hg, with minimal tricuspid regurgitation. EF was 72%. Sulfasalazine 1 g/day was added to methotrexate therapy. Twenty days later, the patient was hospitalized for interstitial nephritis. It did not respond to a steroid treatment, so hemodialysis was started. Unfortunately, the patient died of septic shock due to catheter infection.
Discussion
In our case, initial symptoms of LVDD and pulmonary hypertension began after the second infusion of infliximab and increased after the third infusion. For these reasons, we classified our case as possible infliximab-induced acceleration of LVDD and pulmonary hypertension according to the Naranjo probability scale. 2 On the other hand, despite the disappearance of symptoms, continuation of mild pulmonary hypertension led us to assume that our patient could have had mild pulmonary hypertension prior to treatment. She had RA and hypertension, both of which may lead to LVDD and pulmonary hypertension and are clinically silent until the advanced stages. 3 Therefore, we concluded that infliximab might have aggravated preexisting LVDD and pulmonary hypertension rather than playing a direct role.
TNF-α, in physiologic concentrations, is a protective cytokine for the myocardium. 1 TNF-α can stimulate production of prostaglandin I2, a vasodilator mediator in pulmonary vasculature. 4 Moreover, TNF-α may stimulate production of nitric oxide, 5 another vasodilator mediator in pulmonary vasculature. All these taken into account, we suggest that blockage of TNF-α may have led to adverse effects on the myocardium and PAP in our patient. We believe that TNF-α blockers may have a role in accelerating preexisting LVDD and pulmonary hypertension and that care should be taken with patients with asymptomatic LVDD and pulmonary hypertension.